M Furniss et al. Mutations in AAGAB in Families with Punctate PPK
advantage. Also, it was an advantage that we were able to take within-person correlation into account to avoid artificial estimates. This study also had some limitations. The study population were women who had participated in the first pregnancy interview, which took place early in the second trimester, and the risk of fetal deaths in the first trimester— which constitute the largest proportion of fetal deaths—could therefore not be estimated. In this study, information on psoriasis was self-reported. This could have introduced misclassification of mothers with psoriasis, but it was probably confined to women who had mild psoriasis and were misclassified as unexposed. This might have driven the association toward displaying no difference between women with and without psoriasis. In the DNBC, there was no information on the severity of psoriasis. We had no access to information regarding psoriasis treatment before or during pregnancy. However, most likely only a few women—if any—were given systemic treatments as these treatments are normally avoided for women of childbearing age. An issue when studying TTP, is the fact that only women who achieve pregnancy are included. This excludes a whole group of women who never become pregnant. In conclusion, in this large prospective cohort study we found that psoriasis
was not a risk factor for fetal death after the first trimester or for prolonged TTP in patients with mainly mild to moderate psoriasis. CONFLICT OF INTEREST The authors state no conflict of interest.
ACKNOWLEDGMENTS The Danish National Research Foundation established the Danish Epidemiology Science Center, which initiated and created the Danish National Birth Cohort. The cohort is also a result of a major grant from this foundation. Additional support for the Danish National Birth Cohort has been obtained from the Pharmacy Foundation, the Egmont Foundation, the March of Dimes Birth Defects Foundation, and the Augustinus Foundation.
Elise Harder1, Anne-Marie Nybo Andersen1, Mads Kamper-Jørgensen1 and Lone Skov2 1
Section of Social Medicine, Department of Public Health, University of Copenhagen, Copenhagen, Denmark and 2Department of Dermato-Allergology, Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark E-mail: [email protected] SUPPLEMENTARY MATERIAL Supplementary material is linked to the online version of the paper at http://www.nature.com/jid
REFERENCES Bandoli G, Johnson D, Jones K et al. (2010) Potentially modifiable risk factors for adverse
pregnancy outcomes in women with psoriasis. Br J Dermatol 163:334–9 Ben-David G, Sheiner E, Hallak M et al. (2008) Pregnancy outcome in women with psoriasis. J Reprod Med 53:183–7 Christophers E (2001) Psoriasis—epidemiology and clinical spectrum. Clin Exp Dermatol 26: 314–20 Cohen-Barak E, Nachum Z, Rozenman D et al. (2010) Pregnancy outcomes in women with moderate-to-severe psoriasis. J Eur Acad of Dermatol Venereol 25:1041–7 Jawaheer D, Zhu JL, Nohr EA et al. (2011) Time to pregnancy among women with rheumatoid arthritis. Arthritis Rheum 63:1517–21 Lima XT, Janakiraman V, Huges MD et al. (2012) The impact of psoriasis on pregnancy outcomes. J Invest Dermatol 132:85–91 Lynge E, Sandegaard J, Rebolj M (2011) The Danish National Patient Register. Scand J Public Health 39:30–3 Malgarinos G, Gikas A, Delicha E et al. (2007) Pregnancy and inflammatory bowel disease: a prospective case-control study. Rev Med Chir Soc Med Nat Iasi 111:613–9 Nestle FO, Kaplan DH, Barker J (2009) Mechanisms of disease psoriasis. N Engl J Med 361:496–509 Olsen J, Melbye M, Olsen S et al. (2001) The Danish National Birth Cohort—its background, structure and aim. Scand J Public Health 29:300–7 Pedersen C (2011) The Danish Civil Registration System. Scand J Public Health 39:22–5 WHO (2013) Global database on Body Mass Index. BMI Classification. http://apps.who. int/bmi/index.jsp?intropage=intro_3.html Yang Y-W, Chen C-S, Chen Y-H et al. (2010) Psoriasis and pregnancy outcomes: a nationwide population-based study. J Am Acad Dermatol 64:71–7
Identification of Distinct Mutations in AAGAB in Families with Type 1 Punctate Palmoplantar Keratoderma Journal of Investigative Dermatology (2014) 134, 1749–1752; doi:10.1038/jid.2014.4; published online 30 January 2014
TO THE EDITOR Our understanding of skin biology has been greatly enhanced by studying genodermatoses, as this has guided the discovery of key genes responsible for skin function (Chamcheu et al., 2011). Palmoplantar keratodermas (PPKs) are a
group of rare, heterogeneous hereditary diseases characterized by epidermal hyperkeratosis of palmoplantar skin. They are typically classified according to their mode of inheritance or morphologic features of the disease. However, the clinical picture is often complicated
Abbreviation: PPK/PPKP1, palmoplantar keratoderma/palmoplantar keratoderma, punctate, type 1 Accepted article preview online 3 January 2014; published online 30 January 2014
by significant interfamilial and intrafamilial variation in lesional appearance (Kelsell and Stevens, 1999). In this study, we focused on punctate palmoplantar keratoderma type 1 (PPKP1), also known as punctate PPK, or Buschke–Fischer–Brauer (OMIM 148600). The inheritance of punctate PPK is commonly autosomal dominant; however, it sometimes presents as an acquired disease (Emmert et al., 2003). www.jidonline.org 1749
M Furniss et al. Mutations in AAGAB in Families with Punctate PPK
p.D20Pfs*2 (c.58-68delGACCAGCTGGT)
E1
p.R161X (c.481C>T) p.L99Afs*9 (c.295insG)
E2
p.G158Efs*1 (c.472delG)
E4
E3
p.S189X (c.566C>G)
E8 E7 α and γ-adaptin-binding domain
p.D115Vfs*7 (c.344delA)
p.R124X (c.370C>T)
p.? (c.535+1G>A)
p.R116Sfs*1 (c.348-349delAG) p.C7X (c.21T>A)
E9
E10
p.W130X (c.390G>A)
p.L92Lfs*18 (c.275delT)
p.W47X (c.140G>A)
p.A213Afs*29 (c.639delA)
E6
E5
Rab-like GTPase domain
p.0? (c.2del)
p.N188Sfs*3 (c.562-263insTC)
p.L242X (c.725T>G)
p.F184Lfs*6 (c.552-554TAG>AT)
p.? (c.870+1G>A)
p.L252Lfs*14 (c.755-756insAAGCCAGTCT)
p.S118Kfs*3 (c.352-355delTCTG)
p.F67Lfs*41 (c.200-203delTTCT) p.Q21X (c.61C>T)
Figure 1. Mutations in AAGAB underlie punctate palmoplantar keratoderma (PPK). (a) Representative photographs of patients with punctate PPK. Note the disproportionate involvement of the soles over the palms, and the high degree of phenotypic variability between patients. (b) Summary and location of AAGAB mutations identified within this and previous studies. Mutations on the top half of the diagram are those identified within this study (red indicates novel mutations, whereas black indicates mutations that have been previously described). On the bottom half of the diagram are mutations that have been identified in previous studies. Within the AAGAB protein, the locations of the GTPase and adaptin-binding domains are indicated, as are the locations of the 10 exons.
The onset of punctate PPK is usually observed between 10 and 45 years of age, with the number and severity of lesions increasing with advancing age. Lesions present as multiple small, yellow, hyperkeratotic papules with central indentation and are irregularly distributed. Typically, there is an
increased confluence of lesions over areas of high pressure, such as on the soles of the feet, whereas the punctate morphology is more evident on the palms (Figure 1a). There is an absence of inflammatory changes, and only rarely are there nail findings observed in punctate PPK. Notably, punctate PPK
1750 Journal of Investigative Dermatology (2014), Volume 134
has been reported to be associated with an increased incidence of squamous cell carcinomas, as well as early- and late-onset malignancies, such as Hodgkin’s disease, renal, breast, pancreatic, and colonic adenocarcinomas (Bennion and Patterson, 1984; Kelsell and Stevens, 1999).
M Furniss et al. Mutations in AAGAB in Families with Punctate PPK
Table 1. Summary of mutations in AAGAB gene found in 11 families with punctate PPK DNA mutation
Consequence to protein
Families
Ancestry
c.481C4T1
p.R161X
PPK04, PPK07, PPK08, PPK09
Slovenian and Arab-Israeli
c.566C4G
p.S189X
PPK05, PPK06
Slovenian
p.D20Pfs*2
PPK02
Israeli
c.472delG
p.G158Efs*1
PPK11
Canadian
c.562-563insTC
p.N188Sfs*3
PPK01
Israeli
c.295insG
p.L99Afs*9
PPK12
Israeli
c.639delA
pA213Afs*29
PPK10
Slovenian
c.58-68delGACCAGCTGGT 2
1
Mutation previously reported by Pohler et al., 2012, Giehl et al., 2012, Cui et al., 2013, and Kiritsi et al., 2013. 2 Mutation previously reported by Pohler et al., 2012 and Pohler et al., 2013.
Ten years ago, mutations in more than 15 genes had been identified in different forms of PPK; however, the pathogenic mutations underlying punctate PPK were unknown. We previously reported three large pedigrees from Israel and Mexico, punctate PPK, and mapped the affected locus to chromosome 15q22–24 using linkage analysis (Martinez-Mir et al., 2003). Recently, two groups simultaneously identified several loss-of-function mutations in a single gene, AAGAB, in multiple families of different ancestries with punctate PPK (Giehl et al., 2012; Pohler et al., 2012). AAGAB encodes the a- and g-adaptin-binding protein p34, and is located on chromosome 15q.22, within our previously identified linkage region (Martinez-Mir et al., 2003). Four subsequent studies have described mutations in AAGAB that underlie punctate PPK in several new families (Cui et al., 2013; Kiritsi et al., 2013; Li et al., 2013; Pohler et al., 2013). In light of these findings, we sequenced the whole AAGAB gene in our cohort of 11 families with punctate PPK (Supplementary Figures S1–S11 online). The pedigrees of PPK01– PPK03 were previously documented, in our linkage studies (Martinez-Mir et al., 2003). We sequenced PPK01 and PPK02, which are of Israeli and ArabIsraeli origin, for mutations in AAGAB. Further, we sequenced AAGAB in an additional nine new families with punctate PPK, which were designated PPK04–PPK12. Of these, two were from Israel, one was from Canada, and six were from Slovenia. In Slovenia, the incidence of punctate PPK is 3.3/
100,000, making it extremely prevalent in this population, compared with the twofold lower incidence of 1.17/ 100,000 in the neighboring Croatian population (Stanimirovic et al., 1993; Miljkovic and Kansky, 2009). Genomic DNA was obtained from blood samples collected following informed consent in accordance with IRB regulations at Columbia University and the Declaration of Helsinki Principles. We used Sanger Sequencing to sequence the AAGAB gene in patients from each of our families, using primers previously described for this gene (Pohler et al., 2012). Pedigrees, sequencing results, and photographs of each family can be found in the Supplementary results. We found 7 distinct pathogenic mutations within 11 families, of which 5 are previously unreported to our knowledge (Figure 1b). These were all heterozygous, consistent with an autosomal dominant pattern of inheritance. Mutations segregated with the disease phenotype in all but one unaffected individual where a heterozygous mutation was detected. Presumably this patient had not yet manifested the phenotype (Supplementary Figure S4 online). Of the seven identified mutations (Table 1), we found one, c.481C4T: p.R161X, in four families (three from Slovenia and one from Israel). This mutation was previously described as a founder mutation in families of Croatian origin (Giehl et al., 2012), and was also observed within Scottish and Chinese families (Pohler et al., 2012; Cui et al., 2013; Kiritsi et al., 2013). Moreover, the mutation in our Canadian family,
c.472delG; p.G158Efs*1, was previously found in five families of Scottish origin (Pohler et al., 2012). To our knowledge the other five mutations identified in this study have not been reported elsewhere to date. Of these, one mutation, c.566C4G, p.S189X, was found in two families of Slovenian origin, whereas the remaining four mutations, which were all predicted to cause frameshifts in the protein, were each unique to a single family. Substantial phenotypic variability was noted between patients who carried the same mutation, ranging from very mild to extensively hyperkeratotic presentations of the disease. Although this indicates that environmental factors and personal skin care regimens may affect the degree of hyperkeratosis, it is not uncommon for dominantly inherited diseases to exhibit such variable expressivity. AAGAB consists of 10 exons with a coding sequence of 945 nucleotides, and it codes for the a- and g-adaptin-binding protein p34 (Pohler et al., 2012). p34 has a role in membrane trafficking, and as a result of AAGAB mutations, deficiencies in p34 lead to impaired endocytic recycling of EGFR proteins, which in turn leads to cellular hyperproliferation (Pohler et al., 2012). Cellular hyperproliferation is postulated to be at least one cause of the hyperkeratotic lesions observed in punctate PPK. In summary, to our knowledge we identified five previously unreported mutations and two recurrent mutations of the AAGAB gene, which underlie punctate PPK. There are now a total of 22 mutations in AAGAB that have been www.jidonline.org 1751
O Eytan et al. OS Caused by a Homozygous Recessive Mutation in TRPV3
identified in patients with punctate PPK. Although PPK is a rare disorder, diseases characterized by hyperkeratosis and hyperproliferation are common, and identification of the underlying cellular mechanisms in this familial keratoderma may contribute to our future ability to understand and treat the more prevalent hyperkeratotic diseases.
University, New York, New York, USA; Department of Clinical Medicine, University of Applied Health Sciences, Zagreb, Croatia; 5 Department of Dermatology, Maribor University, Maribor, Slovenia and 6Department of Genetics and Development, Columbia University, New York, New York, USA
CONFLICT OF INTEREST
SUPPLEMENTARY MATERIAL
The authors state no conflict of interest.
ACKNOWLEDGMENTS We are very grateful to the patients and families that participated in this study. We also thank those who participated in the technical support for this study: T Waran Lalin, Y Quin, and HM Lin. This study was supported in part by funding from the NIH/NIAMS (R01-AR44924) to AMC. MF is a trainee on NIH/NIGMS T32GM082771, Medical Genetics Training Program.
Megan Furniss1,7, Claire A. Higgins1,7, Amalia Martinez-Mir1,8, Liran Horev2, Lynn Petukhova1,3, Andrija Stanimirovic´4, Jovan Miljkovic´5, Abraham Zlotogorski2 and Angela M. Christiano1,6 1
Department of Dermatology, Columbia University, New York, New York, USA; 2 Department of Dermatology, HadassahHebrew University Medical Center, Jerusalem, Israel; 3Department of Epidemiology, Columbia
4
8
Current address: Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, Sevilla, Spain. E-mail: [email protected]
Supplementary material is linked to the online version of the paper at http://www.nature.com/jid
REFERENCES Bennion SD, Patterson JW (1984) Keratosis punctata palmaris et plantaris and adenocarcinoma of the colon. A possible familial association of punctate keratoderma and gastrointestinal malignancy. J Am Acad Dermatol 10:587–91
Giehl KA, Eckstein GN, Pasternack SM et al. (2012) Nonsense mutations in AAGAB cause punctate palmoplantar keratoderma type BuschkeFischer-Brauer. Am J Hum Genet 91:754–9 Kelsell DP, Stevens HP (1999) The palmoplantar keratodermas: much more than palms and soles. Mol Med Today 5:107–13 Kiritsi D, Chmel N, Arnold AW et al. (2013) Novel and recurrent AAGAB mutations: clinical variability and molecular consequences. J Invest Dermatol 133:2483–6 Li M, Yang L, Shi H et al. (2013) Loss-of-function mutation in AAGAB in Chinese families with punctuate palmoplantar keratoderma. Br J Dermatol 169:168–71 Martinez-Mir A, Zlotogorski A, Londono D et al. (2003) Identification of a locus for type I punctate palmoplantar keratoderma on chromosome 15q22-q24. J Med Genet 40:872–8 Miljkovic J, Kansky A (2009) Hereditary palmoplantar keratoderma type papulosa in Slovenia. Acta Dermatovenerol Alp Panonica Adriat 18:114–6
Chamcheu JC, Siddiqui IA, Syed DN et al. (2011) Keratin gene mutations in disorders of human skin and its appendages. Arch Biochem Biophys 508:123–37
Pohler E, Mamai O, Hirst J et al. (2012) Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma. Nat Genet 44:1272–6
Cui H, Gao M, Wang W et al. (2013) Six mutations in AAGAB confirm its pathogenic role in Chinese punctate palmoplantar keratoderma patients. J Invest Dermatol 133:2631–4
Pohler E, Zamiri M, Harkins CP et al. (2013) Heterozygous mutations in AAGAB cause type 1 punctate palmoplantar keratoderma with evidence for increased growth factor signaling. J Invest Dermatol 133:2805–8
Emmert S, Kuster W, Hennies HC et al. (2003) 47 patients in 14 families with the rare genodermatosis keratosis punctata palmoplantaris Buschke-Fischer-Brauer. Eur J Dermatol 13: 16–20
Stanimirovic A, Kansky A, Basta-Juzbasic A et al. (1993) Hereditary palmoplantar keratoderma, type papulosa, in Croatia. J Am Acad Dermatol 29:435–7
Olmsted Syndrome Caused by a Homozygous Recessive Mutation in TRPV3 Journal of Investigative Dermatology (2014) 134, 1752–1754; doi:10.1038/jid.2014.37; published online 20 February 2014
TO THE EDITOR Olmsted syndrome (OS; MIM 614594) is a rare genodermatosis featuring symmetric and mutilating palmoplantar keratoderma (PPK) and periorificial keratotic plaques (Olmsted, 1927). Diffuse alopecia, onychodystrophy, oral leucokeratosis, corneal lesions, and pseudoainhum may be associated as well (Mevorah et al., 2005; Lai-Cheong et al., 2012). Extracutaneous manifesta-
tions are uncommon and include deafness, mental retardation, joint laxity, osteopenia, and osteolysis, secondary infections, and squamous cell carcinoma developing in areas of PPK (Mevorah et al., 2005). Although most cases reported to date have been sporadic, both autosomal dominant (Cambiaghi et al., 1995) and X-linked recessive inheritance (Larregue et al., 2000; Haghighi et al., 2013)
Abbreviations: OS, Olmsted syndrome; PPK, palmoplantar keratoderma; RFLP, restriction fragment length polymorphism; TRPV, vanilloid family of transient receptor potential Accepted article preview online 24 January 2013; published online 20 February 2014
1752 Journal of Investigative Dermatology (2014), Volume 134
have been reported and shown to be associated with mutations in TRPV3 (MIM 607066) which encodes the transient receptor potential vanilloid 3 (Lai-Cheong et al., 2012; Lin et al., 2012) and X-linked MBTPS2 (MIM 300294), encoding the membrane-bound transcription factor protease, site 2, respectively (Haghighi et al., 2013). TRPV3 is highly expressed in keratinocytes and in cells outlining hair follicles (Valdes-Rodriguez et al., 2013). It has an important role in epidermal barrier formation (Cheng et al., 2010), modulates hair growth
advantage. Also, it was an advantage that we were able to take within-person correlation into account to avoid artificial estimates. This study also had some limitations. The study population were women who had participated in the first pregnancy interview, which took place early in the second trimester, and the risk of fetal deaths in the first trimester— which constitute the largest proportion of fetal deaths—could therefore not be estimated. In this study, information on psoriasis was self-reported. This could have introduced misclassification of mothers with psoriasis, but it was probably confined to women who had mild psoriasis and were misclassified as unexposed. This might have driven the association toward displaying no difference between women with and without psoriasis. In the DNBC, there was no information on the severity of psoriasis. We had no access to information regarding psoriasis treatment before or during pregnancy. However, most likely only a few women—if any—were given systemic treatments as these treatments are normally avoided for women of childbearing age. An issue when studying TTP, is the fact that only women who achieve pregnancy are included. This excludes a whole group of women who never become pregnant. In conclusion, in this large prospective cohort study we found that psoriasis
was not a risk factor for fetal death after the first trimester or for prolonged TTP in patients with mainly mild to moderate psoriasis. CONFLICT OF INTEREST The authors state no conflict of interest.
ACKNOWLEDGMENTS The Danish National Research Foundation established the Danish Epidemiology Science Center, which initiated and created the Danish National Birth Cohort. The cohort is also a result of a major grant from this foundation. Additional support for the Danish National Birth Cohort has been obtained from the Pharmacy Foundation, the Egmont Foundation, the March of Dimes Birth Defects Foundation, and the Augustinus Foundation.
Elise Harder1, Anne-Marie Nybo Andersen1, Mads Kamper-Jørgensen1 and Lone Skov2 1
Section of Social Medicine, Department of Public Health, University of Copenhagen, Copenhagen, Denmark and 2Department of Dermato-Allergology, Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark E-mail: [email protected] SUPPLEMENTARY MATERIAL Supplementary material is linked to the online version of the paper at http://www.nature.com/jid
REFERENCES Bandoli G, Johnson D, Jones K et al. (2010) Potentially modifiable risk factors for adverse
pregnancy outcomes in women with psoriasis. Br J Dermatol 163:334–9 Ben-David G, Sheiner E, Hallak M et al. (2008) Pregnancy outcome in women with psoriasis. J Reprod Med 53:183–7 Christophers E (2001) Psoriasis—epidemiology and clinical spectrum. Clin Exp Dermatol 26: 314–20 Cohen-Barak E, Nachum Z, Rozenman D et al. (2010) Pregnancy outcomes in women with moderate-to-severe psoriasis. J Eur Acad of Dermatol Venereol 25:1041–7 Jawaheer D, Zhu JL, Nohr EA et al. (2011) Time to pregnancy among women with rheumatoid arthritis. Arthritis Rheum 63:1517–21 Lima XT, Janakiraman V, Huges MD et al. (2012) The impact of psoriasis on pregnancy outcomes. J Invest Dermatol 132:85–91 Lynge E, Sandegaard J, Rebolj M (2011) The Danish National Patient Register. Scand J Public Health 39:30–3 Malgarinos G, Gikas A, Delicha E et al. (2007) Pregnancy and inflammatory bowel disease: a prospective case-control study. Rev Med Chir Soc Med Nat Iasi 111:613–9 Nestle FO, Kaplan DH, Barker J (2009) Mechanisms of disease psoriasis. N Engl J Med 361:496–509 Olsen J, Melbye M, Olsen S et al. (2001) The Danish National Birth Cohort—its background, structure and aim. Scand J Public Health 29:300–7 Pedersen C (2011) The Danish Civil Registration System. Scand J Public Health 39:22–5 WHO (2013) Global database on Body Mass Index. BMI Classification. http://apps.who. int/bmi/index.jsp?intropage=intro_3.html Yang Y-W, Chen C-S, Chen Y-H et al. (2010) Psoriasis and pregnancy outcomes: a nationwide population-based study. J Am Acad Dermatol 64:71–7
Identification of Distinct Mutations in AAGAB in Families with Type 1 Punctate Palmoplantar Keratoderma Journal of Investigative Dermatology (2014) 134, 1749–1752; doi:10.1038/jid.2014.4; published online 30 January 2014
TO THE EDITOR Our understanding of skin biology has been greatly enhanced by studying genodermatoses, as this has guided the discovery of key genes responsible for skin function (Chamcheu et al., 2011). Palmoplantar keratodermas (PPKs) are a
group of rare, heterogeneous hereditary diseases characterized by epidermal hyperkeratosis of palmoplantar skin. They are typically classified according to their mode of inheritance or morphologic features of the disease. However, the clinical picture is often complicated
Abbreviation: PPK/PPKP1, palmoplantar keratoderma/palmoplantar keratoderma, punctate, type 1 Accepted article preview online 3 January 2014; published online 30 January 2014
by significant interfamilial and intrafamilial variation in lesional appearance (Kelsell and Stevens, 1999). In this study, we focused on punctate palmoplantar keratoderma type 1 (PPKP1), also known as punctate PPK, or Buschke–Fischer–Brauer (OMIM 148600). The inheritance of punctate PPK is commonly autosomal dominant; however, it sometimes presents as an acquired disease (Emmert et al., 2003). www.jidonline.org 1749
M Furniss et al. Mutations in AAGAB in Families with Punctate PPK
p.D20Pfs*2 (c.58-68delGACCAGCTGGT)
E1
p.R161X (c.481C>T) p.L99Afs*9 (c.295insG)
E2
p.G158Efs*1 (c.472delG)
E4
E3
p.S189X (c.566C>G)
E8 E7 α and γ-adaptin-binding domain
p.D115Vfs*7 (c.344delA)
p.R124X (c.370C>T)
p.? (c.535+1G>A)
p.R116Sfs*1 (c.348-349delAG) p.C7X (c.21T>A)
E9
E10
p.W130X (c.390G>A)
p.L92Lfs*18 (c.275delT)
p.W47X (c.140G>A)
p.A213Afs*29 (c.639delA)
E6
E5
Rab-like GTPase domain
p.0? (c.2del)
p.N188Sfs*3 (c.562-263insTC)
p.L242X (c.725T>G)
p.F184Lfs*6 (c.552-554TAG>AT)
p.? (c.870+1G>A)
p.L252Lfs*14 (c.755-756insAAGCCAGTCT)
p.S118Kfs*3 (c.352-355delTCTG)
p.F67Lfs*41 (c.200-203delTTCT) p.Q21X (c.61C>T)
Figure 1. Mutations in AAGAB underlie punctate palmoplantar keratoderma (PPK). (a) Representative photographs of patients with punctate PPK. Note the disproportionate involvement of the soles over the palms, and the high degree of phenotypic variability between patients. (b) Summary and location of AAGAB mutations identified within this and previous studies. Mutations on the top half of the diagram are those identified within this study (red indicates novel mutations, whereas black indicates mutations that have been previously described). On the bottom half of the diagram are mutations that have been identified in previous studies. Within the AAGAB protein, the locations of the GTPase and adaptin-binding domains are indicated, as are the locations of the 10 exons.
The onset of punctate PPK is usually observed between 10 and 45 years of age, with the number and severity of lesions increasing with advancing age. Lesions present as multiple small, yellow, hyperkeratotic papules with central indentation and are irregularly distributed. Typically, there is an
increased confluence of lesions over areas of high pressure, such as on the soles of the feet, whereas the punctate morphology is more evident on the palms (Figure 1a). There is an absence of inflammatory changes, and only rarely are there nail findings observed in punctate PPK. Notably, punctate PPK
1750 Journal of Investigative Dermatology (2014), Volume 134
has been reported to be associated with an increased incidence of squamous cell carcinomas, as well as early- and late-onset malignancies, such as Hodgkin’s disease, renal, breast, pancreatic, and colonic adenocarcinomas (Bennion and Patterson, 1984; Kelsell and Stevens, 1999).
M Furniss et al. Mutations in AAGAB in Families with Punctate PPK
Table 1. Summary of mutations in AAGAB gene found in 11 families with punctate PPK DNA mutation
Consequence to protein
Families
Ancestry
c.481C4T1
p.R161X
PPK04, PPK07, PPK08, PPK09
Slovenian and Arab-Israeli
c.566C4G
p.S189X
PPK05, PPK06
Slovenian
p.D20Pfs*2
PPK02
Israeli
c.472delG
p.G158Efs*1
PPK11
Canadian
c.562-563insTC
p.N188Sfs*3
PPK01
Israeli
c.295insG
p.L99Afs*9
PPK12
Israeli
c.639delA
pA213Afs*29
PPK10
Slovenian
c.58-68delGACCAGCTGGT 2
1
Mutation previously reported by Pohler et al., 2012, Giehl et al., 2012, Cui et al., 2013, and Kiritsi et al., 2013. 2 Mutation previously reported by Pohler et al., 2012 and Pohler et al., 2013.
Ten years ago, mutations in more than 15 genes had been identified in different forms of PPK; however, the pathogenic mutations underlying punctate PPK were unknown. We previously reported three large pedigrees from Israel and Mexico, punctate PPK, and mapped the affected locus to chromosome 15q22–24 using linkage analysis (Martinez-Mir et al., 2003). Recently, two groups simultaneously identified several loss-of-function mutations in a single gene, AAGAB, in multiple families of different ancestries with punctate PPK (Giehl et al., 2012; Pohler et al., 2012). AAGAB encodes the a- and g-adaptin-binding protein p34, and is located on chromosome 15q.22, within our previously identified linkage region (Martinez-Mir et al., 2003). Four subsequent studies have described mutations in AAGAB that underlie punctate PPK in several new families (Cui et al., 2013; Kiritsi et al., 2013; Li et al., 2013; Pohler et al., 2013). In light of these findings, we sequenced the whole AAGAB gene in our cohort of 11 families with punctate PPK (Supplementary Figures S1–S11 online). The pedigrees of PPK01– PPK03 were previously documented, in our linkage studies (Martinez-Mir et al., 2003). We sequenced PPK01 and PPK02, which are of Israeli and ArabIsraeli origin, for mutations in AAGAB. Further, we sequenced AAGAB in an additional nine new families with punctate PPK, which were designated PPK04–PPK12. Of these, two were from Israel, one was from Canada, and six were from Slovenia. In Slovenia, the incidence of punctate PPK is 3.3/
100,000, making it extremely prevalent in this population, compared with the twofold lower incidence of 1.17/ 100,000 in the neighboring Croatian population (Stanimirovic et al., 1993; Miljkovic and Kansky, 2009). Genomic DNA was obtained from blood samples collected following informed consent in accordance with IRB regulations at Columbia University and the Declaration of Helsinki Principles. We used Sanger Sequencing to sequence the AAGAB gene in patients from each of our families, using primers previously described for this gene (Pohler et al., 2012). Pedigrees, sequencing results, and photographs of each family can be found in the Supplementary results. We found 7 distinct pathogenic mutations within 11 families, of which 5 are previously unreported to our knowledge (Figure 1b). These were all heterozygous, consistent with an autosomal dominant pattern of inheritance. Mutations segregated with the disease phenotype in all but one unaffected individual where a heterozygous mutation was detected. Presumably this patient had not yet manifested the phenotype (Supplementary Figure S4 online). Of the seven identified mutations (Table 1), we found one, c.481C4T: p.R161X, in four families (three from Slovenia and one from Israel). This mutation was previously described as a founder mutation in families of Croatian origin (Giehl et al., 2012), and was also observed within Scottish and Chinese families (Pohler et al., 2012; Cui et al., 2013; Kiritsi et al., 2013). Moreover, the mutation in our Canadian family,
c.472delG; p.G158Efs*1, was previously found in five families of Scottish origin (Pohler et al., 2012). To our knowledge the other five mutations identified in this study have not been reported elsewhere to date. Of these, one mutation, c.566C4G, p.S189X, was found in two families of Slovenian origin, whereas the remaining four mutations, which were all predicted to cause frameshifts in the protein, were each unique to a single family. Substantial phenotypic variability was noted between patients who carried the same mutation, ranging from very mild to extensively hyperkeratotic presentations of the disease. Although this indicates that environmental factors and personal skin care regimens may affect the degree of hyperkeratosis, it is not uncommon for dominantly inherited diseases to exhibit such variable expressivity. AAGAB consists of 10 exons with a coding sequence of 945 nucleotides, and it codes for the a- and g-adaptin-binding protein p34 (Pohler et al., 2012). p34 has a role in membrane trafficking, and as a result of AAGAB mutations, deficiencies in p34 lead to impaired endocytic recycling of EGFR proteins, which in turn leads to cellular hyperproliferation (Pohler et al., 2012). Cellular hyperproliferation is postulated to be at least one cause of the hyperkeratotic lesions observed in punctate PPK. In summary, to our knowledge we identified five previously unreported mutations and two recurrent mutations of the AAGAB gene, which underlie punctate PPK. There are now a total of 22 mutations in AAGAB that have been www.jidonline.org 1751
O Eytan et al. OS Caused by a Homozygous Recessive Mutation in TRPV3
identified in patients with punctate PPK. Although PPK is a rare disorder, diseases characterized by hyperkeratosis and hyperproliferation are common, and identification of the underlying cellular mechanisms in this familial keratoderma may contribute to our future ability to understand and treat the more prevalent hyperkeratotic diseases.
University, New York, New York, USA; Department of Clinical Medicine, University of Applied Health Sciences, Zagreb, Croatia; 5 Department of Dermatology, Maribor University, Maribor, Slovenia and 6Department of Genetics and Development, Columbia University, New York, New York, USA
CONFLICT OF INTEREST
SUPPLEMENTARY MATERIAL
The authors state no conflict of interest.
ACKNOWLEDGMENTS We are very grateful to the patients and families that participated in this study. We also thank those who participated in the technical support for this study: T Waran Lalin, Y Quin, and HM Lin. This study was supported in part by funding from the NIH/NIAMS (R01-AR44924) to AMC. MF is a trainee on NIH/NIGMS T32GM082771, Medical Genetics Training Program.
Megan Furniss1,7, Claire A. Higgins1,7, Amalia Martinez-Mir1,8, Liran Horev2, Lynn Petukhova1,3, Andrija Stanimirovic´4, Jovan Miljkovic´5, Abraham Zlotogorski2 and Angela M. Christiano1,6 1
Department of Dermatology, Columbia University, New York, New York, USA; 2 Department of Dermatology, HadassahHebrew University Medical Center, Jerusalem, Israel; 3Department of Epidemiology, Columbia
4
8
Current address: Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, Sevilla, Spain. E-mail: [email protected]
Supplementary material is linked to the online version of the paper at http://www.nature.com/jid
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Giehl KA, Eckstein GN, Pasternack SM et al. (2012) Nonsense mutations in AAGAB cause punctate palmoplantar keratoderma type BuschkeFischer-Brauer. Am J Hum Genet 91:754–9 Kelsell DP, Stevens HP (1999) The palmoplantar keratodermas: much more than palms and soles. Mol Med Today 5:107–13 Kiritsi D, Chmel N, Arnold AW et al. (2013) Novel and recurrent AAGAB mutations: clinical variability and molecular consequences. J Invest Dermatol 133:2483–6 Li M, Yang L, Shi H et al. (2013) Loss-of-function mutation in AAGAB in Chinese families with punctuate palmoplantar keratoderma. Br J Dermatol 169:168–71 Martinez-Mir A, Zlotogorski A, Londono D et al. (2003) Identification of a locus for type I punctate palmoplantar keratoderma on chromosome 15q22-q24. J Med Genet 40:872–8 Miljkovic J, Kansky A (2009) Hereditary palmoplantar keratoderma type papulosa in Slovenia. Acta Dermatovenerol Alp Panonica Adriat 18:114–6
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Olmsted Syndrome Caused by a Homozygous Recessive Mutation in TRPV3 Journal of Investigative Dermatology (2014) 134, 1752–1754; doi:10.1038/jid.2014.37; published online 20 February 2014
TO THE EDITOR Olmsted syndrome (OS; MIM 614594) is a rare genodermatosis featuring symmetric and mutilating palmoplantar keratoderma (PPK) and periorificial keratotic plaques (Olmsted, 1927). Diffuse alopecia, onychodystrophy, oral leucokeratosis, corneal lesions, and pseudoainhum may be associated as well (Mevorah et al., 2005; Lai-Cheong et al., 2012). Extracutaneous manifesta-
tions are uncommon and include deafness, mental retardation, joint laxity, osteopenia, and osteolysis, secondary infections, and squamous cell carcinoma developing in areas of PPK (Mevorah et al., 2005). Although most cases reported to date have been sporadic, both autosomal dominant (Cambiaghi et al., 1995) and X-linked recessive inheritance (Larregue et al., 2000; Haghighi et al., 2013)
Abbreviations: OS, Olmsted syndrome; PPK, palmoplantar keratoderma; RFLP, restriction fragment length polymorphism; TRPV, vanilloid family of transient receptor potential Accepted article preview online 24 January 2013; published online 20 February 2014
1752 Journal of Investigative Dermatology (2014), Volume 134
have been reported and shown to be associated with mutations in TRPV3 (MIM 607066) which encodes the transient receptor potential vanilloid 3 (Lai-Cheong et al., 2012; Lin et al., 2012) and X-linked MBTPS2 (MIM 300294), encoding the membrane-bound transcription factor protease, site 2, respectively (Haghighi et al., 2013). TRPV3 is highly expressed in keratinocytes and in cells outlining hair follicles (Valdes-Rodriguez et al., 2013). It has an important role in epidermal barrier formation (Cheng et al., 2010), modulates hair growth
